Guidance for design and analysis of observational studies of fetal and newborn outcomes following COVID-19 vaccination during pregnancy

Abstract

COVID-19 vaccines are now being deployed as essential tools in the public health response to the global SARS-CoV-2 pandemic. Pregnant individuals are a unique subgroup of the population with distinctive considerations regarding risk and benefit that extend beyond themselves to their fetus/newborn. As a complement to traditional pharmacovigilance and clinical studies, evidence to comprehensively assess COVID-19 vaccine safety in pregnancy will need to be generated through observational epidemiologic studies in large populations. However, there are several unique methodological challenges that face observational assessments of vaccination during pregnancy, some of which may be more pronounced for COVID-19 studies. In this contribution, we discuss the most critical study design, data collection, and analytical issues likely to arise. We offer brief guidance to optimize the quality of such studies to ensure their maximum value for informing public health decision-making.

Keywords: COVID-19 vaccination; Pregnancy; Vaccine safety.

Fig. 1

(A) Illustration of immortal time for individuals 1 and 2 (time prior to vaccination is incorrectly classified as “exposed” based on final vaccination status at delivery). (B) Corrected classification of time for individuals 1 and 2 (time prior to vaccination is classified as “unexposed” [dashed line] and exposure status changes to “exposed” [solid line] at time of vaccination). (C) Illustration of possible exposure classification scenarios for two-dose COVID-19 vaccines, showing different gestational ages and intervals between doses. Solid lines represent “exposed”time (following dose 2 of a two-dose vaccine). Dashed lines represent “unexposed”time. Dotted lines representtime after dose 1 but before dose 2 of a two-dose vaccine. Note that Individual 8 in Panel C received the first dose prior to pregnancy and the second dose during early pregnancy (perhaps even before pregnancy recognition), requiring one change in exposure status from post-dose 1 to post-dose 2 (there would be no vaccine-unexposed time). Figure adapted from Platt et al..

Fig. 2

Timing of pregnancies relative to hypothetical outbreak dynamics and periods of limited and widespread COVID-19 vaccination. Horizontal grey bars depict full-term pregnancies occurring throughout the COVID-19 pandemic time period. Line graph portrays outbreak dynamics. Blue shaded zones illustrate potential vaccine delivery time periods.